Short-term anti-vascular endothelial growth factor treatment elicits vasculogenic mimicry formation of tumors to accelerate metastasis

Abstract

Background: Antiangiogenic therapy is one of the most significant advances in anticancer treatment. The benefits of antiangiogenic therapies of late-stage cancers have been investigated but are still too limited. Methods:We used an ovarian cancer model to test the effect of short-term bevacizumab treatment on metastasis as measured by bioluminescence. Western blotting and CD34-PAS dual staining were performed to assess hypoxiainducible transcription factor-1α (HIF-1α) expression and vasculogenic mimicry(VM) formation. Cell viability was examined by a CCK8 assay.Results: Bevacizumab demonstrated antitumor effects in models of ovarian cancer, but also accelerated metastasis together, with marked hypoxia and VM formation in mice receiving short-term therapy. Bevacizumab treatment did not affect SKOV3 cell viability and the amount of VM in three-dimensional culture. Conclusion: These results suggest that antiangiogenic therapy may potentially influence the progression of metastatic disease, which has been linked to the hypoxic response and VM formation.

Monitoring hypoxia and vasculature during bevacizumab treatment in a murine colorectal cancer model

“…In contrast, other hypotheses claim that bevacizumab may lead to the formation of inadequate tumor vessels, inducing tumor hypoxia and necrosis . Although inadequate vasculature and tumor hypoxia may subsequently lead to tumor necrosis, induction of hypoxia could also drive progression toward a more aggressive tumor phenotype . Hypoxic tumors are less responsive to systemic therapy and radiation therapy .…”

Novel Pathways for Targeting Tumor Angiogenesis in Metastatic Breast Cancer

“…In patients with colorectal cancer, the process of vessel co-option has been linked to poor responses to anti-angiogenic therapies like Bevacizumab ( 42 ). The trans-differentiated endothelial-like cancer cells that drive vascular mimicry have also shown limited sensitivity to anti-angiogenic therapeutics ( 55 , 82 ), with tumors that are resistant to these therapies exhibiting higher levels of vascular mimicry ( 83 ).…”